Blood-Derived DNA Methylation Markers of Cancer Risk

  • Carmen Marsit
  • Brock Christensen
Part of the Advances in Experimental Medicine and Biology book series (volume 754)


The importance of somatic epigenetic alterations in tissues targeted for carcinogenesis is now well recognized and considered a key molecular step in the development of a tumor. Particularly, alteration of gene-specific and genomic DNA methylation has been extensively characterized in tumors, and has become an attractive biomarker of risk due to its specificity and stability in human samples. It also is clear that tumors do not develop as isolated phenomenon in their target tissue, but instead result from altered processes affecting not only the surrounding cells and tissues, but other organ systems, including the immune system. Thus, alterations to DNA methylation profiles detectable in peripheral blood may be useful not only in understanding the carcinogenic process and response to environmental insults, but can also provide critical insights in a systems biological view of tumorigenesis. Research to date has generally focused on how environmental exposures alter genomic DNA methylation content in peripheral blood. More recent work has begun to translate these findings to clinically useful endpoints, by defining the relationship between DNA methylation alterations and cancer risk. This chapter highlights the existing research linking the environment, blood-derived DNA methylation alterations, and cancer risk, and points out how these epigenetic alterations may be contributing fundamentally to carcinogenesis.


Bladder Cancer Risk Global Methylation Bisulfite Pyrosequencing BRCA1 Methylation Blood Methylation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Alexander RP, Fang G et al (2010) Annotating non-coding regions of the genome. Nat Rev Genet 11(8):559–571PubMedCrossRefGoogle Scholar
  2. 2.
    Ally MS, Al-Ghnaniem R et al (2009) The relationship between gene-specific DNA methylation in leukocytes and normal colorectal mucosa in subjects with and without colorectal tumors. Cancer Epidemiol Biomarkers Prev 18(3):922–928PubMedCrossRefGoogle Scholar
  3. 3.
    Al-Moghrabi N, Al-Qasem AJ et al (2011) Methylation-related mutations in the BRCA1 promoter in peripheral blood cells from cancer-free women. Int J Oncol 39(1):129–135PubMedGoogle Scholar
  4. 4.
    Baccarelli A, Wright RO et al (2009) Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med 179(7):572–578PubMedCrossRefGoogle Scholar
  5. 5.
    Barker DJ (2004) Developmental origins of adult health and disease. J Epidemiol Community Health 58(2):114–115PubMedCrossRefGoogle Scholar
  6. 6.
    Barker DJ (2004) The developmental origins of well-being. Philos Trans R Soc Lond B Biol Sci 359(1449):1359–1366PubMedCrossRefGoogle Scholar
  7. 7.
    Bennett KL, Mester J et al (2010) Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA 304(24):2724–2731PubMedCrossRefGoogle Scholar
  8. 8.
    Bibikova M, Lin Z et al (2006) High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16(3):383–393PubMedCrossRefGoogle Scholar
  9. 9.
    Birgisdottir V, Stefansson OA et al (2006) Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast cancer research: BCR 8(4):R38PubMedCrossRefGoogle Scholar
  10. 10.
    Bollati V, Baccarelli A et al (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67(3):876–880PubMedCrossRefGoogle Scholar
  11. 11.
    Bosviel R, Michard E et al (2011) Peripheral blood DNA methylation detected in the BRCA1 or BRCA2 promoter for sporadic ovarian cancer patients and controls. Clin Chim Acta 412(15–16):1472–1475PubMedCrossRefGoogle Scholar
  12. 12.
    Butcher DT, Rodenhiser DI (2007) Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours. Eur J Cancer 43(1):210–219PubMedCrossRefGoogle Scholar
  13. 13.
    Cash HL, Tao L et al (2011) LINE-1 hypomethylation is associated with bladder cancer risk among nonsmoking Chinese. Int J Cancer 130(5):1151–1159PubMedCrossRefGoogle Scholar
  14. 14.
    Chan TL, Yuen ST et al (2006) Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 38(10):1178–1183PubMedCrossRefGoogle Scholar
  15. 15.
    Choi JY, James SR et al (2009) Association between global DNA hypomethylation in leukocytes and risk of breast cancer. Carcinogenesis 30(11):1889–1897PubMedCrossRefGoogle Scholar
  16. 16.
    Christensen BC, Houseman EA et al (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5(8):e1000602PubMedCrossRefGoogle Scholar
  17. 17.
    Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10(10):691–703PubMedCrossRefGoogle Scholar
  18. 18.
    Deininger PL, Batzer MA (1999) Alu repeats and human disease. Mol Genet Metab 67(3): 183–193PubMedCrossRefGoogle Scholar
  19. 19.
    Dewannieux M, Esnault C et al (2003) LINE-mediated retrotransposition of marked Alu sequences. Nat Genet 35(1):41–48PubMedCrossRefGoogle Scholar
  20. 20.
    Dobrovic A, Kristensen LS (2009) DNA methylation, epimutations and cancer predisposition. Int J Biochem Cell Biol 41(1):34–39PubMedCrossRefGoogle Scholar
  21. 21.
    Eads CA, Danenberg KD et al (2000) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28(8):E32PubMedCrossRefGoogle Scholar
  22. 22.
    Flanagan JM, Munoz-Alegre M et al (2009) Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients. Hum Mol Genet 18(7):1332–1342PubMedCrossRefGoogle Scholar
  23. 23.
    Florl AR, Lower R et al (1999) DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas. Br J Cancer 80(9):1312–1321PubMedCrossRefGoogle Scholar
  24. 24.
    Fraga MF, Ballestar E et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102(30):10604–10609PubMedCrossRefGoogle Scholar
  25. 25.
    Futreal PA, Liu Q et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182):120–122PubMedCrossRefGoogle Scholar
  26. 26.
    Gama-Sosa MA, Wang RY et al (1983) The 5-methylcytosine content of highly repeated sequences in human DNA. Nucleic Acids Res 11(10):3087–3095PubMedCrossRefGoogle Scholar
  27. 27.
    Gaudet F, Hodgson JG et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300(5618):489–492PubMedCrossRefGoogle Scholar
  28. 28.
    Gicquel C, Rossignol S et al (2005) Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 37(9):1003–1007PubMedCrossRefGoogle Scholar
  29. 29.
    Hajkova P, Erhardt S et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117(1–2):15–23PubMedCrossRefGoogle Scholar
  30. 30.
    Herman JG, Graff JR et al (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93(18):9821–9826PubMedCrossRefGoogle Scholar
  31. 31.
    Hitchins MP (2010) Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet 70:201–243PubMedCrossRefGoogle Scholar
  32. 32.
    Hitchins M, Williams R et al (2005) MLH1 germline epimutations as a factor in hereditary nonpolyposis colorectal cancer. Gastroenterology 129(5):1392–1399PubMedCrossRefGoogle Scholar
  33. 33.
    Hitchins MP, Wong JJ et al (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356(7):697–705PubMedCrossRefGoogle Scholar
  34. 34.
    Hitchins M, Owens S et al (2011) Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort(dagger). Clin Genet 80(5):428–434PubMedCrossRefGoogle Scholar
  35. 35.
    Hou L, Wang H et al (2010) Blood leukocyte DNA hypomethylation and gastric cancer risk in a high-risk Polish population. Int J Cancer 127(8):1866–1874PubMedCrossRefGoogle Scholar
  36. 36.
    Hsiung DT, Marsit CJ et al (2007) Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 16(1):108–114PubMedCrossRefGoogle Scholar
  37. 37.
    Iwamoto T, Yamamoto N et al (2011) BRCA1 promoter methylation in peripheral blood cells is associated with increased risk of breast cancer with BRCA1 promoter methylation. Breast Cancer Res Treat 129(1):69–77PubMedCrossRefGoogle Scholar
  38. 38.
    Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21(2):163–167PubMedCrossRefGoogle Scholar
  39. 39.
    Jordan IK, Rogozin IB et al (2003) Origin of a substantial fraction of human regulatory sequences from transposable elements. Trends Genet 19(2):68–72PubMedCrossRefGoogle Scholar
  40. 40.
    Koestler DC, Marsit CJ et al (2010) Semi-supervised recursively partitioned mixture models for identifying cancer subtypes. Bioinformatics 26(20):2578–2585PubMedCrossRefGoogle Scholar
  41. 41.
    Kolomietz E, Meyn MS et al (2002) The role of Alu repeat clusters as mediators of recurrent chromosomal aberrations in tumors. Genes Chromosomes Cancer 35(2):97–112PubMedCrossRefGoogle Scholar
  42. 42.
    Lancaster JM, Wooster R et al (1996) BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13(2):238–240PubMedCrossRefGoogle Scholar
  43. 43.
    Lander ES, Linton LM et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921PubMedCrossRefGoogle Scholar
  44. 44.
    Langevin SM, Koestler DC et al (2012) Peripheral blood DNA methylation profiles are predictive of head and neck squamous cell carcinoma: an epigenome-wide association study. Epigenetics 7(3):291–299PubMedCrossRefGoogle Scholar
  45. 45.
    Lee J, Inoue K et al (2002) Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129(8):1807–1817PubMedGoogle Scholar
  46. 46.
    Li W, Deng J et al (2010) Association of 5′-CpG island hypermethylation of the FHIT gene with lung cancer in southern-central Chinese population. Cancer Biol Ther 10(10):997–1000PubMedCrossRefGoogle Scholar
  47. 47.
    Lim U, Flood A et al (2008) Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology 134(1):47–55PubMedCrossRefGoogle Scholar
  48. 48.
    Liu Z, Zhao J et al (2008) CpG island methylator phenotype involving tumor suppressor genes located on chromosome 3p in non-small cell lung cancer. Lung Cancer 62(1):15–22PubMedCrossRefGoogle Scholar
  49. 49.
    Liu Z, Li W et al (2010) CpG island methylator phenotype involving chromosome 3p confers an increased risk of non-small cell lung cancer. J Thorac Oncol 5(6):790–797PubMedCrossRefGoogle Scholar
  50. 50.
    Marsit CJ, Koestler DC et al (2011) DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol 29(9): 1133–1139PubMedCrossRefGoogle Scholar
  51. 51.
    McCarthy MI, Hirschhorn JN (2008) Genome-wide association studies: potential next steps on a genetic journey. Hum Mol Genet 17(R2):R156–R165PubMedCrossRefGoogle Scholar
  52. 52.
    McKay JD, Truong T et al (2011) A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet 7(3):e1001333PubMedCrossRefGoogle Scholar
  53. 53.
    Menendez L, Benigno BB et al (2004) L1 and HERV-W retrotransposons are hypomethylated in human ovarian carcinomas. Mol Cancer 3:12PubMedCrossRefGoogle Scholar
  54. 54.
    Moore LE, Pfeiffer RM et al (2008) Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case–control study. Lancet Oncol 9(4):359–366PubMedCrossRefGoogle Scholar
  55. 55.
    Morak M, Schackert HK et al (2008) Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. Eur J Hum Genet 16(7):804–811PubMedCrossRefGoogle Scholar
  56. 56.
    Nelson HH, Marsit CJ et al (2011) “Global methylation” in exposure biology and translational medical science. Environ Health Perspect 119(11):1528–1533PubMedCrossRefGoogle Scholar
  57. 57.
    Netchine I, Rossignol S et al (2007) 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 92(8):3148–3154PubMedCrossRefGoogle Scholar
  58. 58.
    Pavanello S, Bollati V et al (2009) Global and gene-specific promoter methylation changes are related to anti-B[a]PDE-DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon-exposed individuals. Int J Cancer 125(7):1692–1697PubMedCrossRefGoogle Scholar
  59. 59.
    Pedersen KS, Bamlet WR et al (2011) Leukocyte DNA methylation signature differentiates pancreatic cancer patients from healthy controls. PLoS One 6(3):e18223PubMedCrossRefGoogle Scholar
  60. 60.
    Pufulete M, Al-Ghnaniem R et al (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124(5): 1240–1248PubMedCrossRefGoogle Scholar
  61. 61.
    Roupret M, Hupertan V et al (2008) Promoter hypermethylation in circulating blood cells identifies prostate cancer progression. Int J Cancer 122(4):952–956PubMedCrossRefGoogle Scholar
  62. 62.
    Rusiecki JA, Baccarelli A et al (2008) Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect 116(11): 1547–1552PubMedCrossRefGoogle Scholar
  63. 63.
    Sano H, Imokawa M et al (1988) Detection of heavy methylation in human repetitive DNA subsets by a monoclonal antibody against 5-methylcytosine. Biochim Biophys Acta 951(1): 157–165PubMedCrossRefGoogle Scholar
  64. 64.
    Snell C, Krypuy M et al (2008) BRCA1 promoter methylation in peripheral blood DNA of mutation negative familial breast cancer patients with a BRCA1 tumour phenotype. Breast Cancer Res 10(1):R12PubMedCrossRefGoogle Scholar
  65. 65.
    Steenman MJ, Rainier S et al (1994) Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms’ tumour. Nat Genet 7(3):433–439PubMedCrossRefGoogle Scholar
  66. 66.
    Suter CM, Martin DI et al (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36(5):497–501PubMedCrossRefGoogle Scholar
  67. 67.
    Suter CM, Martin DI et al (2004) Hypomethylation of L1 retrotransposons in colorectal cancer and adjacent normal tissue. Int J Colorectal Dis 19(2):95–101PubMedCrossRefGoogle Scholar
  68. 68.
    Tarantini L, Bonzini M et al (2009) Effects of particulate matter on genomic DNA methylation content and iNOS promoter methylation. Environ Health Perspect 117(2):217–222PubMedGoogle Scholar
  69. 69.
    Teschendorff AE, Menon U et al (2009) An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One 4(12):e8274PubMedCrossRefGoogle Scholar
  70. 70.
    Thompson ME, Jensen RA et al (1995) Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9(4):444–450PubMedCrossRefGoogle Scholar
  71. 71.
    Ting DT, Lipson D et al (2011) Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science 331(6017):593–596PubMedCrossRefGoogle Scholar
  72. 72.
    Vineis P, Chuang SC et al (2011) DNA methylation changes associated with cancer risk factors and blood levels of vitamin metabolites in a prospective study. Epigenetics 6(2):195–201PubMedCrossRefGoogle Scholar
  73. 73.
    Wang L, Aakre JA et al (2010) Methylation markers for small cell lung cancer in peripheral blood leukocyte DNA. J Thorac Oncol 5(6):778–785PubMedCrossRefGoogle Scholar
  74. 74.
    Weisenberger DJ, Campan M et al (2005) Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33(21):6823–6836PubMedCrossRefGoogle Scholar
  75. 75.
    Widschwendter M, Apostolidou S et al (2008) Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study. PLoS One 3(7):e2656PubMedCrossRefGoogle Scholar
  76. 76.
    Wilhelm CS, Kelsey KT et al (2010) Implications of LINE1 methylation for bladder cancer risk in women. Clin Cancer Res 16(5):1682–1689PubMedCrossRefGoogle Scholar
  77. 77.
    Wong IH, Lo YM et al (2000) Frequent p15 promoter methylation in tumor and peripheral blood from hepatocellular carcinoma patients. Clin Cancer Res 6(9):3516–3521PubMedGoogle Scholar
  78. 78.
    Wong EM, Southey MC et al (2011) Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 4(1):23–33CrossRefGoogle Scholar
  79. 79.
    Wu HC, Delgado-Cruzata L et al (2011) Global methylation profiles in DNA from different blood cell types. Epigenetics 6(1):76–85PubMedCrossRefGoogle Scholar
  80. 80.
    Yang AS, Estecio MR et al (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32(3):e38PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyDartmouth Medical SchoolHanoverUSA
  2. 2.Department of Community and Family Medicine, Section of Biostatistics and EpidemiologyDartmouth Medical SchoolHanoverUSA

Personalised recommendations